Camptothecin, a plant alkaloid isolated from trees indigenous to China, and analogs thereof such as 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 10,11-methylenedioxycamptothecin, 9-nitro-10,11-methylenedioxycamptothecin, 9-chloro-10,11-methylenedioxycamptothecin, 9-amino-10,11-methylenedioxycamptothecin, 7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, DX-8951, Lurtotecan (GI147221C), and other analogs (collectively referred to herein as camptothecin drugs) are presently under study worldwide in research laboratories and cancer clinics. In lab tests and in clinical trials, these camptothecin drugs have aroused considerable interest as a result of their ability to halt the growth of a wide range of human tumors. For example, these drugs exhibit unprecedented high levels of antitumor activities against human colon cancer [Giovanella, et al. Science 246: 1046-1048 (Washington, D.C.) (1989)]. Camptothecin drugs have also been shown to be effective against other experimental cancer types such as lung, breast, and malignant melanoma.
Camptothecin drugs are thought to inhibit the proliferation of cancer cells by interfering with the breakage/reunion reaction of the enzyme topoisomerase I, a nuclear enzyme implicated in DNA replication and RNA transcription. A camptothecin drug stabilizes and forms a reversible enzyme-camptothecin-DNA ternary complex, designated the cleavage complex. The formation of the cleavable complex specifically prevents the reunion step of the breakage/union cycle of the topoisomerase reaction. Topoisomerase I inhibitors are also known to be useful in the treatment of HIV.
Camptothecin and homocamptothecin both contain five-membered ring systems as shown below. ##STR1##
For both camptothecin (top structure) and homocamptothecin (bottom structure), Z=hydrogen. Unfortunately, camptothecin/homocamptothecin and many structurally-related camptothecin analogs/derivatives are water-insoluble. This water insolubility makes administration of camptothecin drugs difficult. In an effort to address this problem a number of synthetic efforts have been directed to derivatizing the A-ring and/or B-ring to improve water-solubility while maintaining cytotoxic activity.
To date, some water-soluble camptothecin derivatives have been prepared by derivatizing the A and B rings and by opening the lactone E-ring. See, for example, U.S. Pat. Nos. 5,646,159, 5,559,235, 5,670,500, 5,663,177, 5,677,286, and 5,734,056. U.S. Pat. No. 5,646,159 discloses water-soluble pro-drug type camptothecin compounds, in which the 20-position hydroxyl group is esterified. Enzymes present within the body can break the ester bond after injection to form the parent camptothecin compound.
U.S. Pat. No. 5,559,235 discloses water-soluble camptothecin compounds, in which the A ring has 10,11-ethylene or methylenedioxy rings and substituents at C-7. U.S. Pat. No. 5,670,500 discloses water-soluble camptothecin drugs, in which the A ring is connected to the substituted furan-ring. U.S. Pat. No. 5,663,177 discloses water-soluble camptothecin analogs, in which the A- and B rings are connected with a heterocyclic ring containing nitrogen. U.S. Pat. No. 5,677,286 discloses water-soluble camptothecin analogs in which the A ring has non-ionic sugar moieties, which increase the water solubility. U.S. Pat. No. 5,734,056 discloses the process for the preparation of 10-hydroxy-9-alkyl analogs of camptothecin.
A need continues to exist for the development of new and better camptothecin and homocamptothecin compounds having still higher antitumor activity and still more improved water-solubility while exhibiting low levels of toxicity.